Polyoxaester suspending vehicles for use with implantable delivery systems

ABSTRACT

Liquid polyoxaester polymer materials are provided as suspending vehicles suitable for dispensing of pharmaceutically active agents, such as proteins, from delivery devices, for example, pump-driven dosage forms. Polyoxaesters are made from at least one diacid and at least one diol. Through the use of polyoxaesters virtually solvent-free pharmaceutical suspensions can be created.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/374,228, filed on 13 Mar. 2006, now U.S. Pat. No. 7,959,938, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/662,091,filed on 15 Mar. 2005, which applications are herein incorporated byreference in their entireties in the present application.

FIELD OF THE INVENTION

The present invention relates to suspending vehicles and pharmaceuticalsuspensions in drug delivery systems and drug dosage forms utilizing thesame.

BACKGROUND OF THE INVENTION

Ensuring stability of pharmaceutical agents within dosage forms thatinclude suspensions is important, for example, for effective dosagingand/or shelf-stability. Pharmaceutical suspensions can be used, forexample, in osmotic drug delivery devices and injection depot devices.Osmotically-driven, also referred to as pump-driven, devices includethose described in U.S. Pat. Nos. 5,985,305; 6,113,938; 6,132,420;6,156,331; 6,395,292; each of which is incorporated herein by reference.

One approach to providing a stable suspension of a pharmaceutical agentis to provide a dosage form containing a suspending vehicle whoseviscosity is sufficiently high to slow the sedimentation rate of thepharmaceutical agent. Typically, suspending vehicles contain a highviscosity, biocompatible polymer and a water-immiscible solvent.Water-immiscible solvents are typically chosen for their tendency tolimit water ingress into drug dosage forms that are exposed to aqueousmedia, for example, bodily fluids. Such solvents have been shown toprovide stable environments for pharmaceutically active agents such asproteins and peptides.

Some biocompatible polymers, such as polyvinyl pyrolidone (PVP), exhibitsome amount of solubility in water. As such, some suspending vehiclesseparate into two phases at an organic/aqueous interface at outlets ofdosage forms. Under certain conditions, suspending vehicles comprisingpolymer in conjunction with a water-immiscible solvent may be difficultto pump through narrow exit ports of dosage forms. Further, reliabilityof dosage forms can be compromised by the formation of highly viscous,almost solid formations.

Hence, there exists a need to provide suspending vehicles made of aprimary component that provides a stable environment for proteins andpeptides that is substantially solvent-free. Also, there is a need toeliminate pluggage of discharge ports of implantable devices.Additionally, there is a need for suspending vehicles that use a primarycomponent which exhibit desirable suspension characteristics while atthe same time remain one-phase upon contact with aqueous media.

SUMMARY OF THE INVENTION

Generally, certain aspects of the invention provide pharmaceuticalsuspensions having polyoxaesters (POEs) as suspending vehicles.Polyoxaesters provide suitable characteristics for suspension andstability of pharmaceutically active agents, such as proteins, peptides,and small molecules, for use in conjunction with pump-driven dosagesforms. Typically, vehicles and suspensions are substantially non-aqueousin order to maintain drug stability during storage and to limit ingressof water into the dosage forms.

In one aspect, the present invention provides pharmaceutical suspensionsfor use in pump-driven pharmaceutical dosage forms which comprise apharmaceutically active agent and a polyoxaester. The polyoxaesterscomprise reaction products of at least one diacid and at least one diol.In a detailed embodiment, the polyoxaesters have molecular weights fromapproximately 1,000 to approximately 100,000.

Preferable diacids for use with the present invention include, but arenot limited to, polyglycolic diacids, 3,6-trioxaundecanedioic diacids,3,6,9-trioxaundecanedioic diacids, and combinations thereof.

Preferable diols for use with the present invention include, but are notlimited to, ethyleneglycols, propanediols, butanediols, pentanediols,cyclopentanediol, hexanediols, cyclohexanediols, octanediols,decanediols, dodecanediols, cyclohexanedimethanol, polyethyleneglycol,polypropyleneglycol, and combinations thereof.

In a detailed embodiment of the invention, a dosage form is providedthat comprises a first wall that maintains its physical and chemicalintegrity during the life of the dosage form and is substantiallyimpermeable to a pharmaceutical suspension; a second wall that ispartially permeable to an exterior fluid; a compartment defined by thefirst wall and the second wall; a pharmaceutical suspension that ispositioned within the compartment and comprises a pharmaceuticallyactive agent and a polyoxaester; a pump in communication with the firstwall, the second wall, and the compartment; and an exit port incommunication with the compartment. Preferably, the dosage formcomprises an osmotic pump.

Also, in certain aspects, the pharmaceutical suspension is substantiallyflowable through the exit port of a dosage form under a force exerted bythe pump under normal operating conditions.

Other examples of the present invention include pharmaceuticalsuspensions that are substantially homogeneous for at least 3 months at37° C.

Methods include administering dosage forms containing pharmaceuticalsuspensions having polyoxaesters as suspending vehicles to a mammal.Kits include such dosage forms and instructions for theiradministration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a starting monomer for POEs: 3,6,9-trioxaundecanedioicacid.

FIG. 2 shows a starting monomer for POEs: polyglycolic diacid.

FIG. 3 shows viscosity versus shear rate for one batch of POE II, andthe viscosity is 100 poise at 35° C.

FIG. 4 shows viscosity versus temperature of for the same batch of POEII as shown in FIG. 3 (100 poise at 35° C.).

FIG. 5 shows viscosity versus shear rate for a second batch of POE II,and the viscosity is 1000 poise at 35° C.

FIG. 6 shows viscosity versus temperature for the same batch of POE IIas shown in FIG. 5 (1000 poise at 35° C.).

FIG. 7 shows a release rate profile of 7 wt % lysozyme in the 1000 poise(35° C.)-POE II.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Liquid polyoxaester polymer materials are provided as suspendingvehicles suitable for dispensing of pharmaceutically active agents, suchas proteins, from delivery devices, for example, pump-driven dosageforms. Through the use of polyoxaesters (POEs), virtually solvent-freepharmaceutical suspensions can be created that exhibit virtually nophase separation at exit ports of pump-driven, for example, anosmotically-driven pump, dosage forms. Also, the formulation ofone-component vehicles that are virtually solvent-free is simplifiedcompared to multi-component formulations because only one component isneeded.

Generally, polyoxaesters are biodegradable polymers that are formed bycondensation reactions of oxadiacids and diols. Typically, polyoxaestersare one-phase, one-component liquid polymers that do not immediatelyharden or phase invert upon contact with aqueous media or duringhydrolysis. Such polyoxaester polymers are also desirable due to theminimal aggregation of proteins therein. Polyoxaesters are absorbable bymammals, for example, they polymers hydrolyze into acids and alcoholswithin a few days. The POEs also do not accumulate in the body. Proteinsare released relatively easily from a POE environment, relative to otherpolymer-based suspending vehicles which contain solvents, for example,benzyl alcohol with polyvinyl pyrrolidone. POEs tend to remain misciblewith water or to stay soft when contacted with water. Also, POEs aredesirable in the ability to control their viscosity at 35° C. based onreaction time.

With reference to FIG. 1, 3,6,9-trioxaundecanedioic acid is a preferablestarting monomer for the POEs of the present invention. This monomer canbe combined with at least one diol to create a POE polymer. “POE I”means a polymer derived from a mixture of 3,6,9-trioxaundecanedioic acidand ethyleneglycol as the starting monomers. With reference to FIG. 2,polyglycolic diacid is another preferable starting monomer for the POEsof the present invention. This monomer can be combined with at least onediol to create a POE polymer. “POE II” means a polymer derived from amixture of polyglycolic diacid as a starting monomer.

Reference to “suspending vehicle” means that the pharmaceutically activeagent is substantially insoluble therein. Materials that aresubstantially insoluble generally remain substantially in their originalphysical form throughout the lifespan of a dosage form containing thesuspension. For example, solid particulates would generally remainparticles. If necessary, the suspending vehicle may have other materialsdissolved in it.

Although traditionally, in order to prevent particles in pharmaceuticalsuspensions from settling during the useful life of a dosage form,suspending vehicles having viscosities on the order of 10,000 poise at35° C. were desirable. The settling rate of the particles isproportional to the density difference between the particle and thesuspending medium. As such, lower viscosity-polymers can be used whenthey have densities that are substantially the same, or close, totypical protein particle densities, for example 1.2 g/mL. POE's of thepresent invention have densities that are close to densities of typicalprotein particles. As such, a lower viscosity may be sufficient toprevent particle settling during storage and use of a pharmaceuticalimplant.

Reference to “flowable” means that the suspending vehicles andpharmaceutical suspensions are able to flow out of a dosage form despitethe possible presence of a second phase. As such, although somepolymer-based gels may be present in the vehicles and suspensions uponcontact with an aqueous medium, the vehicles and suspensions aresubstantially free of stiff gels, that is free of gels that are hardenough to impede flow out of the dosage form. Hence, although gels maybe present, they are sufficiently pliable to permit the vehicle orsuspension to flow out of the dosage form, for example, an osmoticdosage form. Preferably, suspending vehicles and pharmaceuticalsuspensions according to the present invention remain flowable uponcontact with an aqueous medium under normal operating conditions of thedosage form.

Reference to “substantially free of solvents” means that the inpharmaceutical suspension that there is minimal use of solvents of thetype that are typically used to thin highly viscous polymers for usesuspending vehicles.

Polymers

Polymers useful in forming a vehicle according to the present inventioninclude, but are not limited to, POE liquid polymers that result fromcondensation reactions of at least one diacid and at least one diol.Preferable diacids include, but are not limited to, polyglycolic diacid,3,6-trioxaundecanedioic acid, 3,6,9-trioxaundecanedioic acid, andcombinations thereof. Preferable diols include, but are not limited to,ethyleneglycols, propanediols, butanediols, pentanediols,cyclopentanediol, hexanediols, cyclohexanediols, octanediols,decanediols, dodecanediols, cyclohexanedimethanol, polyethyleneglycol,polypropyleneglycol, and combinations thereof. In some aspects of theinvention, the molar ratio of the diacid to diol in the final polymer isapproximately 1:1. Typically, during the reaction, the molar ratio ofdiacid to diol is <1. As such the molar ratio during the reaction isinitially preferably approximately 1:2. Excess diol can be removed asneeded, for example, by vacuum processing. In a detailed embodiment, thepolyoxaesters have molecular weights ranging from approximately 1,000 toapproximately 100,000.

Other examples of polymers useful in forming a pharmaceutical suspensionor suspending vehicle according to the present invention include, butare not limited to, the polyoxaester polymers disclosed by U.S. Pat.Nos. 5,464,929; 5,607,687; 5,618,552; 5,620,698; 5,648,088; 5,859,150;6,147,168; and 6,224,894 each of which is incorporated herein byreference. It may also be desirable to use polyoxaesters that containamines and/or amido groups, for example, polyoxaamides, including, butnot limited to polymers disclosed by U.S. Pat. Nos. 5,595,751;5,597,579; 5,620,698; 5,645,850; 5,648,088; 5,844,017; 6,074,660; and6,100,346.

Pharmaceutically Active Agents

“Pharmaceutically active agent” refers to any biologically orpharmacologically active substance or antigen-comprising material; theterm includes drug substances which have utility in the treatment orprevention of diseases or disorders affecting animals or humans, or inthe regulation of any animal or human physiological condition and italso includes any biologically active compound or composition which,when administered in an effective amount, has an effect on living cellsor organisms.

Pharmaceutical suspensions can be created by mixing the pharmaceuticallyactive agent with the suspending vehicle. In some embodiments, thepharmaceutically active agent included in a suspension according to thepresent invention is generally degradable in water but generally stableas a dry powder at ambient and physiological temperatures. Active agentsthat may be incorporated into a suspension according to the inventioninclude, but are not limited to, peptides, proteins, nucleotides,polymers of amino acids or nucleic acid residues, hormones, viruses,antibodies, or small molecules etc. that are naturally derived,synthetically produced, or recombinantly produced. Preferablypharmaceutical suspensions remain substantially homogenous for about 3months, even more preferably for about 6 months, and yet even morepreferably, for about 1 year.

Preferably, the pharmaceutically active agent comprises lysozyme,interferon, erythropoietin, granulocyte macrophage colony stimulatingfactor (GM-CSF), human growth hormone releasing hormone (huGHRH),insulin, desmopressin, infliximab, an antibody, an agent conjugated to atargeting ligand, bone morphogenic proteins, Nesiritide,alpha-interferon, beta-interferon, omega-interferon, adrenocorticotropichormone, angiotensin I, angiotensin II, atrial natriuretic peptide,bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alphaendorphin, beta endorphin, endothelin, enkephalin, epidermal growthfactor, fertirelin, follicular gonadotropin releasing peptide, galanin,glucagon, glucagon-like peptide-1 (GLP-1), gonadorelin, gonadotropin,goserelin, growth hormone releasing peptide, histrelin, human growthhormone, insulin, leuprolide, LHRH, motilin, nafarerlin, neurotensin,oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor,triptorelin, vasopressin, nerve growth factor, blood clotting factors,ribozymes, antisense oligonucleotide, or combinations thereof.

In other embodiments, the pharmaceutically active agent comprisesrisperidone, paliperidone, ocaperidone, or combinations thereof.

Other desirable active substances to all aspects of the invention can bethe so-called antiherpes virus agents which have been or are developedfor the treatment of herpes virus infections [herpes simplex virus types1 and 2 (HSV-1 and HSV-2)], varicella zoster virus (VZV),cytomegalovirus (CMV), Epstein-Barr virus (EBV)]. The antiherpes virusagents include antiviral drugs and prodrugs thereof, such asnucleosides, nucleoside analogues, phosphorylated nucleosides(nucleotides), nucleotide analogues and salts, complexes and prodrugsthereof; e.g., guanosine analogues, deoxyguanosine analogues, guanine,guanine analogues, thymidine analogues, uracil analogues and adenineanalogues. Antiherpes virus agent for use either alone or in combinationin a composition according to the present invention can be selected fromacyclovir, famciclovir, deciclovir, penciclovir, zidovudin, ganciclovir,didanosin, zalcitabin, valaciclovir, sorivudine, lobucavir, brivudine,cidofovir, n-docosanol, ISIS-2922, and salts, prodrugs, derivatives,analogues, and combinations thereof.

Other drugs which in themselves have a low water solubility, or thesalts, esters, prodrugs or precursors of which have a low solubility mayalso be desirable in the compositions of the invention. Furthermore, itmay be desirable to combine some active ingredients. As such, any of theforegoing examples can either alone or in combination can beincorporated in a composition according to the present invention. Forexample, a combination of active ingredients may include an anti-herpesvirus agent and a glucocorticosteroid.

With respect to pharmaceutically active agents, pharmaceuticalsuspensions located in pump-driven dosage forms preferably comprise fromabout 0.5% to about 15% pharmaceutically active agent by weight, andpossibly from about 0.1% to about 30%.

Pharmaceutical suspensions according to the present invention mayinclude any pharmaceutically active agent that either exhibits desiredsolubility characteristics or may be prepared as a particulate materialexhibiting desired solubility characteristics. Agents may be provided inthe form of pharmaceutically acceptable salts, including salts withinorganic acids, organic acids, inorganic bases, organic bases, orcombinations thereof. In some aspects, the agents are a biomolecularmaterial, such as a peptide or protein that has biological activity orthat may be used to treat a disease or other pathological condition.Analogs, derivatives, antagonists, and agonists of the exemplarypeptides and proteins described may also be used. Agents are not limitedto a biomolecular material. The drug may be any compound or material,including any medicine, vitamin, nutrient, or food supplement, which iscapable of providing a therapeutic or beneficial affect whenadministered to an environment of operation and can be prepared as aparticulate material exhibiting desired solubility characteristics.

The active agents included in a suspension according to the presentinvention may also include lipoproteins and post translationallymodified forms, e.g., glycosylated proteins, as well as proteins orprotein substances which have D-amino acids, modified, derivatized ornon-naturally occurring amino acids in the D- or L-configuration and/orpeptomimetic units as part of their structure. Specific examples ofmaterials that may be included in as the pharmaceutically active agentin a suspension of the present invention include, but are not limitedto, baclofen, GDNF, neurotrophic factors, conatonkin G, Ziconotide,clonidine, axokine, anitsense oligonucleotides, adrenocorticotropichormone, angiotensin I and II, atrial natriuretic peptide, bombesin,bradykinin, calcitonin, cerebellin, dynorphin N, alpha and betaendorphin, endothelin, enkephalin, epidermal growth factor, fertirelin,follicular gonadotropin releasing peptide, galanin, glucagon,gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide,histrelin, insulin, interferons, leuprolide, LHRH, motilin, nafarerlin,neurotensin, oxytocin, relaxin, somatostatin, substance P, tumornecrosis factor, triptorelin, vasopressin, growth hormone, nerve.growthfactor, blood clotting factors, ribozymes, and antisenseoligonucleotides. Analogs, derivatives, antagonists agonists andpharmaceutically acceptable salts of each of the above mentioned activeagents may also be used in formulating an active agent suspension of thepresent invention. Preferably, the active agents provided in asuspension of the present invention exhibits little or no solubility inthe chosen suspension vehicle.

The active agents can be in various forms, such as uncharged molecules,molecular complexes, pharmacologically acceptable acid or base additionsalts such as hydrochlorides, hydrobromides, sulfate, laurylate,palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate,oleate, and salicylate. For acidic drugs, salts of metals, amines ororganic cations, for example quaternary ammonium can be used.Derivatives of drugs such as esters, ethers and amides can be used aloneor mixed with other drugs. Also, a drug that is water insoluble can beused in a form that on its release from a device, is converted byenzymes, hydrolyzed by body pH or other metabolic processes to theoriginal form, or to a biologically active form.

With respect to pharmaceutically acceptable excipients and otherprocessing aids, it is preferable that the drug particles incorporateany such excipients and/or aids into the solid drug particulate to bedelivered from a suspension dosage form. As such, reference to drugparticles or pharmaceutically active agents, includes any suchexcipients or aids incorporated therein.

Other desirable pharmaceutically active agents include, but are notlimited to, the following groups: sodium fluoride, anti-inflammatorydrugs such as, e.g., ibuprofen, indomethacin, naproxen, diclofenac,tolfenamic acid, piroxicam, and the like; narcotic antagonists such as,e.g., naloxone, nalorphine, and the like; antiparkinsonism agents suchas, e.g., bromocriptine, biperidin, benzhexol, benztropine, and thelike; antidepressants such as, e.g., imipramine, nortriptyline,pritiptylene, and the like; antibiotic agents such as, e.g.,clindamycin, erythromycin, fusidic acid, gentamicin, mupirocien,amfomycin, neomycin, metronidazole, silver sulphadiazine,sulphamethizole, bacitracin, framycetin, polymycin B, acitromycin, andthe like; antifungal agents such as, e.g., miconazol, ketoconazole,clotrimazole, amphotericin B, nystatin, mepyramin, econazol, fluconazol,flucytocine, griseoftdvin, bifonazole, amorolfine, mycostatin,itraconazole, terbenafine, terconazole, tolnaftate, and the like;antimicrobial agents such as, e.g., metronidazole, tetracyclines,oxytetracycline, and the like; antiemetics such as, e.g.,metoclopramide, droperidol, haloperidol, promethazine, and the like;antihistamines such as, e.g., chlorpheniramine, terfenadine,triprolidine, and the like; antimigraine agents such as, e.g.,dihydroergotamine, ergotamine, pizotyhne, and the like; coronary,cerebral or peripheral vasodilators such as, e.g., nifedipine,diltiazem, and the like; antianginals such as, e.g., glyceryl nitrate,isosorbide denitrate, molsidomine, verapamil, and the like; calciumchannel blockers such as, e.g., verapamil, nifedipine, diltiazem,nicardipine, and the like; hormonal agents such as, e.g., estradiol,estron, estriol, polyestradiol, polyestriol, dienestrol,diethylstilbestrol, progesterone, dihydroergosterone, cyproterone,danazol, testosterone, and the like; contraceptive agents such as, e.g.,ethynyl estradiol, lynestrenol, etynodiol, norethisterone, mestranol,norgestrel, levonorgestrel, desogestrel, medroxyprogesterone, and thelike; antithrombotic agents such as, e.g., heparin, warfarin, and thelike; diuretics such as, e.g., hydrochlorothiazide, flunarizine,minoxidil, and the like; antihypertensive agents such as, e.g.,propanolol, metoprolol, clonidine, pindolol, and the like;corticosteroids such as, e.g., beclomethasone, betamethasone,betamethasone-17-valerate, betamethasone-dipropionate, clobetasol,clobetasol-17-butyrate, clobetasol-propionate, desonide,desoxymethasone, dexamethasone, diflucortolone, flumethasone,flumethasone-pivalate, fluocinolone acetonide, fluocinonide,hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-buteprate,methylprednisolone, triamcinolone acetonide, budesonide, halcinonide,fluprednide acetate, alklometasone-dipropionate, fluocortolone,fluticason-propionate, mometasone-furate, desoxymethasone,diflurason-diacetate, halquinol, cliochinol, chlorchinaldol,fluocinolone-acetonid, and the like; dermatological agents such as,e.g., nitrofurantoin, dithranol, clioquinol, hydroxyquinoline,isotretionin, methoxsalen, methotrexate, tretionin, trioxsalen,salicylic acid, penicillamine, and the like; steroids such as, e.g.,estradiol, progesterone, norethindrone, levonorgestrol, ethynodiol,levenorgestrel, norgestimate, gestanin, desogestrel,3-keton-desogestrel, demegestone, promethoestrol, testosterone,spironolactone, and esters thereof, nitro compounds such as, e.g., amylnitrates, nitroglycerine and isosorbide nitrates, opioid compounds suchas, e.g., morphine and morphine-like drugs such as buprenorphine,oxymorphone, hydromorphone, levorphanol, fentanyl and fentanylderivatives and analogues, prostaglandins such as, e.g., a member of thePGA, PGB, PGE, or PGF series such as, e.g., misoprostol, dinoproston,carboprost or enaprostil, a benzamide such as, e.g., metoclopramide,scopolamine, a peptide such as, e.g., growth hormone releasing factors,growth factors (epidermal growth factor (EGF), nerve growth factor(NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor(FGFα, FGFβ, etc.), and the like), somatostatin, calcitonin, insulin,vasopressin, interferons, interleukins, e.g., IL-2, IL-12, IL-21,urokinase, serratiopeptidase, superoxide dismutase (SOD), thyrotropinreleasing hormone (TRH), luteinizing hormone releasing hormone (LH-RH),corticotrophin releasing hormone (CRF), growth hormone releasing hormone(GHRH), oxytocin, erythropoietin (EPO), colony stimulating factor (CSF),and the like, a xanthine such as, e.g., caffeine, theophylline, acatecholamine such as, e.g., ephedrine, salbutamol, terbutaline, adihydropyridine such as, e.g., nifedipine, a thiazide such as, e.g.,hydrochlorotiazide, flunarizine, others such as, e.g., propanthelin,silver nitrate, enzymes like Streptokinases, Streptodases, vitamins likevitamin A, tretionin, isotretionin, acitretin, vitamin D, calcipotriol,interferon-α-2b, selen disulfide, pyrethione.

It will be understood that the compositions of the invention can alsocomprise combinations of active substances, e.g., an active substancetogether with a potentiator therefor. It will of course also beunderstood that in the aspects of the invention wherein there is nospecific requirement to the active substance, e.g., with respect tosolubility, any substance which has a therapeutic or prophylacticactivity can be incorporated in the composition.

Dosage Forms

Suspending vehicles and pharmaceutical suspensions can be prepared foruse in all types of dosage forms, e.g., oral suspensions, ophthalmologicsuspensions, implant suspensions, injection suspensions, and infusionsuspensions. A preferred dosage form is an implantable osmotic dosageform such as those described in U.S. Pat. Nos. 5,985,305; 6,113,938;6,132,420; 6,156,331; 6,395,292; each of which is incorporated herein byreference. Typically, the implantable osmotic dosage form is afluid-imbibing system that comprises an impermeable reservoir. The wallof the impermeable reservoir defines a first wall. The reservoir isdivided into two chambers or compartments by a piston. The first chambercontains the pharmaceutically active agent and the second chambercontains a fluid-imbibing agent. A back-diffusion regulating outlet,comprising an exit port, is inserted into the open end of the firstcompartment and a water-swellable semi-permeable plug is inserted intothe open end of the second chamber. The piston and the fluid-imbibingagent are components of an osmotic pump. The semi-permeable membranedefines a second wall. In general, the release rate of the active agentis governed by the osmotic pumping rate.

Typically, the implantable osmotic dosage form is a fluid-imbibingsystem that comprises an impermeable reservoir. The wall of theimpermeable reservoir defines a first wall. The reservoir is dividedinto two chambers or compartments by a piston. The first chambercontains the pharmaceutically active agent and the second chambercontains a fluid-imbibing agent. A back-diffusion regulating outlet,comprising an exit port, is inserted into the open end of the firstcompartment and a water-swellable semi-permeable plug is inserted intothe open end of the second chamber. The piston and the fluid-imbibingagent are components of an osmotic pump. The semi-permeable membranedefines a second wall. In general, the release rate of the active agentis governed by the osmotic pumping rate.

It is preferable that the polymers are physiologically acceptable for adesired route of administration, for example, there are no adversebiological responses by the recipient of the suspension uponadministration. In some embodiments of the present invention, it ispreferable that the components are suitable for parenteral routes ofadministration, including but not limited to injection, infusion, orimplantation.

EXAMPLES

Below are several examples of specific embodiments for carrying out thepresent invention. The examples are offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way.

Example 1

Several POE liquid polymers were prepared and physical properties wereanalyzed as shown in Table 1. The polymers were prepared generally bymixing the desired molar ratios of the diacid(s) and diol(s) monomersand a catalyst in a 2 neck, round bottom flask, under a nitrogen purgeand heating the mixture to ˜160° C. slowly. The catalyst was dibutyltinoxide added at a ratio of 1 mole of catalyst to 30,000 mole monomer.Reactions typically started with a nominal molar ratio of approximately1:2 diacid:diol, with the excess diol being removed under vacuum toresult in a polymer that was approximately 1:1 diacid:diol.

The mixture was held at 160° C. for ˜24 hours. The temperature was thenraised to 180° C. and held there for ˜24 hours. The mixture temperaturewas then reduced to 80° C. while vacuum was pulled slowly. Upon a vacuumof ˜50 mTorr, the temperature was increased to 160° C. for 2-3 days.Temperature was increased to 190° C. for a few hours until the samplebecame dark brown and viscous.

The methods disclosed by U.S. Pat. Nos. 5,464,929; 5,607,687; 5,618,552;5,703,200; 5,859,150 6,147,168; 6,224,894; 6,403,655, each of which isincorporated herein by reference, can be used.

Onset of freezing was analyzed visually for the one sample, referred toas “POE I,” which had a polymer composition of 1:1 molar of3,6,9trioxaundecanedioic acid and ethylene glycol.

Visual analysis of the onset of freezing was also used to evaluate thetwo samples referred to as “POE II,” each of which had a polymercomposition of 1:1 molar ratio of polyglycolic diacid andethyleneglycol. As reaction time varies for polymers havingapproximately the same composition, the resulting molecular weights andviscosities will differ.

The other samples were analyzed using DSC, which is differentialscanning calorimetry. Temperature is slowly increased (or decreased) andthe changes in heat capacity of the sample material are monitored. Inthis way, DSC can measure phase transition temperatures.

TABLE 1 POE Polymers Polymer Composition Diacid:Diol Molar RatioViscosity nominal at starting Diacid Diol Onset of 35° C. ratio Mol %Mol % freezing (poise) 1:2 100% 100% Phase change 1,000 polyglycolicethyleneglycol between diacid 5-15° C. 1:2 100% 100% Below 5° C., 100polyglycolic ethyleneglycol if any. diacid 1:2 100% 3, 6, 9 100% Phasechange 3,500 trioxaun- ethyleneglycol between decanedioic 5-25° C. acid1:2 100% 100% 20° C. 507 polyglycolic ethyleneglycol by DSC diacid 1:2100% 100% 20° C. 707 polyglycolic ethyleneglycol by DSC diacid 1:2 100% 75% 22° C. 429 polyglycolic ethyleneglycol by DSC diacid & 25%butanediol 1:2 100% 100% 17° C. 547 polyglycolic hexanediol by DSCdiacid 1:2  75% 100% 18° C. 5,730 polyglycolic ethyleneglycol by DSCdiacid & 25% 3, 6, 9 trioxaun- decanedioic acid 1:2  50% 100% Nofreezing. 5,220 polyglycolic ethyleneglycol Tg~−47° C. diacid & 50% byDSC 3, 6, 9 trioxaun- decanedioic acid

Example 2

POE I, a liquid polymer made from 3,6,9trioxaundecanedioic acid andethylene glycol, made in accordance with Example 1, was used as thesuspending vehicle for a pharmaceutical suspension. The density of POE Iwas 1.29 g/mL+/−1-0.010. The method for measuring density of thesuspension vehicle included taking an aliquot (e.g. 10 μL) of thesuspension vehicle (POE), which was accurately weighed (using a balancewith an accuracy of ±0.01 mg). The value for the density of the samplewas derived from the resultant weight over the volume of the sampletaken (g/mL). The measurement was repeated three times and the averagevalue of the three measurements and the standard deviation reported.

The inherent viscosity of POE I was 0.37 dL/g as determined in HFIP at25° C. and at a concentration of 0.1 g/dL. Average moisture of the POE Isamples was 0.19% and the average peroxide level was 8.21 ppm.

Lysozyme particles were prepared by spray-drying an aqueous lysozymesolution. Lysozyme particles were collected and contained inlyophiliation vials in a low humidity environment. The POE I and thespray-dried lysozyme particles were weighed out according to aparticle-loading of approximately 10% by weight of the pharmaceuticalsuspension, which corresponded to an active agent loading ofapproximately 10% by weight. The ingredients were mixed together withsmall spatula at room temperature in a dry box.

Release of protein from the suspension was determined in aqueousconditions and after undergoing an organic extraction. The POE I-basedpharmaceutical suspension showed 91+/−1.3% released protein, based onultraviolet (UV) absorbance, after 24 hours of incubation in a phosphatebuffer solution at 37° C. The method for this in vitro protein releasetesting at 37° C. included dispensing approximately 10 mg of protein(lysozyme) pharmaceutical suspension in 3 mL of PBS buffer. Thebuffer/suspension mixture was incubated overnight at 37±1° C. incubatorwith constant shaking rate (Lindberg Blue water bath/shaker, speed setat 5). The process yielded a clear solution. The solution was filteredthrough a 0.2 μm membrane, diluted accordingly, and the protein contentdetermined by UV and the purity by RP HPLC.

The percent of protein recovered by organic extraction was 90+/−1%,based on UV measurement. The method for protein extraction from thesuspension using organic solvent included adding pre-chilled THF/acetone50/50 (v/v) solvent mixture (e.g. 0.5 mL)) to the protein (lysozyme)pharmaceutical suspension (e.g. 10 mg). The solvent/suspension mixturewas chilled on ice for a total of 30 min (with occasional mixing). Thesolvent/suspension mixture was spin-filtered through a 0.2 μm membraneto obtain a protein pellet. The retained protein pellet was air-dried,reconstituted in H₂O (e.g. 0.5 mL), mixed well, and allowed to sit at2-8° C. for 1 hour. The clear protein solution was further dilutedaccordingly, and the protein content of the sample determined by UV, andthe degree of protein degradation (purity) by reversed phase highperformance chromatography (RP HPLC). The protein purity was determinedto be 90% whether aqueous or organic environments were used to extractthe lysozyme.

Example 3

POE II, a liquid polymer made from polyglycolic diacid and ethyleneglycol, having a viscosity of 100 poise (35° C.), made in accordancewith Example 1, was used as the suspending vehicle for a pharmaceuticalsuspension. As shown in FIG. 3, there was no effect of shear rate onviscosity. FIG. 4 shows that no phase change occurred between 5° C. and60° C., therefore, a phase change, if any, would occur at <5° C.

The density of the 100 poise (35° C.)-POE II was 1.18 g/mL+/−0.006. Themethod for measuring the density was as described in Example 2. Theinherent viscosity of 100 poise POE II was 0.30 dL/g as determined inHFIP at 25° C. and at a concentration of 0.1 g/dL.

Average moisture of the 100 poise POE II samples was 0.11% and theaverage peroxide level was 6.44 ppm.

Lysozyme particles are prepared by spray-drying an aqueous lysozymesolution. Lysozyme particles are collected and contained inlyophiliation vials in a low humidity environment. The 100 poise (35°C.)-POE II and the spray-dried lysozyme particles were weighed outaccording to a particle-loading of approximately 10% by weight of thepharmaceutical suspension, which corresponded to an active agent loadingof approximately 10% by weight. The ingredients were mixed together withsmall spatula at room temperature in a dry box.

Release of protein from the suspension was determined in aqueousconditions and after undergoing an organic extraction. The 100 poise(35° C.)-POE II-based pharmaceutical suspension showed 90+/−0.3%released protein, based on UV, after 24 hours of incubation in aphosphate buffer solution at 37° C. The method for protein releasetesting at 37° C. was as described in Example 2.

The percent of protein recovered by organic extraction was 97+/−2%,based on UV. The method for extraction of the protein was as describedin Example 2.

Proteins are stable in the 100 poise (35° C.)-POE II-basedpharmaceutical suspension as indicated by RP-HPLC measurements. Thesemeasurements indicate that the purity of the lysozyme is 90% and 95%,after aqueous and organic extraction, respectively.

Example 4

POE II, a liquid polymer made from polyglycolic diacid and ethyleneglycol, having a viscosity of 1000 poise (35° C.), made in accordancewith Example 1, was used as the suspending vehicle for a pharmaceuticalsuspension. As shown in FIG. 5, there was no effect of shear rate onviscosity. FIG. 6 shows the temperature effects on the viscosity of thepolymer. Between 5° C. and 15° C., viscosity increased to unmeasurablevalues, and therefore, a phase change would occur at some point between5° C. and 15° C.

The density of the 1000 poise (35° C.)-POE II was 1.18 g/mL+/−0.003. Themethod for measuring the density was as described in Example 2.

The inherent viscosity of 1000 poise POE II was 0.47 dL/g as determinedin HFIP at 25° C. and at a concentration of 0.1 g/dL. Average moistureof the 1000 poise POE II samples was 0.07% and the average peroxidelevel was 3.79 ppm.

Lysozyme particles are prepared by spray-drying an aqueous lysozymesolution. Lysozyme particles are collected and contained inlyophiliation vials in a low humidity environment. The POE II and thespray-dried lysozyme particles were weighed out according to aparticle-loading of approximately 10% by weight of the pharmaceuticalsuspension, which corresponded to an active agent loading ofapproximately 10% by weight. The ingredients were mixed together withsmall spatula at room temperature in a dry box.

Release of protein from the suspension was determined in aqueousconditions and after undergoing an organic extraction. The POE II-basedpharmaceutical suspension showed 92+/−1.5% released protein, based onUV, after 24 hours of incubation in a phosphate buffer solution at 37°C. The method for protein release testing at 37° C. was as described inExample 2.

The percent of protein recovered by organic extraction was 93+/−1%,based on UV. The method for extraction of the protein was as describedin Example 2. The HPLC measurements indicate that the purity of thelysozyme is 90% and 95%, after aqueous and organic extraction,respectively.

In vitro testing of a pharmaceutical suspension having a lysozymeloading of approximately 7% by weight in the 1000 poise (35° C.)-POE IIwas performed using DUROS implants. This suspension was loaded into 10implantable, pump-driven dosage forms of the type disclosed in U.S. Pat.No. 6,395,292 for example. The release of the pharmaceutically activeagent, for example, lysozyme, from the dosage form was determinedanalytically with UltraViolet spectrophotometry, and the integrity ofthe system as a whole was be observed visually.

First for each dosage form, a subassembly was prepared. A reservoir anda piston were lubricated. The piston was then inserted into thereservoir, followed by two osmotic tablets. Appropriate membranes werepressed into titanium reservoirs.

The pharmaceutical suspension was loaded into 5 ml SGE glass syringes tobe de-aerated by mixing under heat and vacuum. Individual reservoirassemblies of the implantable devices were filled with the suspension.

The subassembly was heated to about 40° C. in a reservoir heater for atleast 5 minutes, and then a diffusion moderator (DM) was put into theend of reservoir.

Ultraviolet-visible (UV) spectrometry was used to determine proteincontent delivered by the dosage forms. The method included the steps asdescribed in Example 2.

As of day 33, 9 of the 10 dosage forms were delivering lysozyme. Asshown in FIG. 7, a substantially zero-order delivery profile over a fourweek time period was achieved.

All publications, patents and patent applications cited herein arehereby incorporated by reference in their entirety. As used in thisspecification and the appended claims, the singular forms “a,” “an” and“the” include plural references unless the content clearly dictatesotherwise.

Other aspects of the invention will be apparent from review of thepresent specification and claims and all such falling within the spiritof the invention are comprehended hereby.

What is claimed:
 1. An implantable osmotic dosage form comprising: apharmaceutical suspension comprising (i) particles comprising a proteinor peptide, and (ii) a suspending vehicle comprising a polyoxaesterhaving a density of about 1.2 g/mL, wherein the pharmaceuticalsuspension is substantially homogeneous for at least 3 months at 37° C.;a first wall that maintains its physical and chemical integrity and issubstantially impermeable to a pharmaceutical suspension; a second wallthat is partially permeable to an exterior fluid; an osmotic pump incontact with the first wall and the second wall; a compartment definedby the first wall and the osmotic pump, wherein the pharmaceuticalsuspension is positioned within the compartment; and an exit port incommunication with the compartment, wherein the pharmaceuticalsuspension is flowable through the exit port under a force exerted bythe osmotic pump.
 2. A method of making the dosage form of claim 1comprising, loading the pharmaceutical suspension into the compartment.3. The dosage form of claim 1, wherein the pharmaceutical suspension issubstantially free of solvents.
 4. The dosage form of claim 1, whereinthe polyoxaester comprises reaction products of at least one diacid andat least one diol.
 5. The dosage form of claim 4, wherein the diacid isselected from the group consisting of a polyglycolic diacid; a3,6-trioxaundecanedioic diacid; a 3,6,9-trioxaundecanedioic diacid; andcombinations thereof.
 6. The dosage form of claim 4, wherein the diol isselected from the group consisting of an ethyleneglycol, a propanediol,a butanediol, a pentanediol, a cyclopentanediol, a hexanediol, acyclohexanediol, an octanediol, a decanediol, a dodecanediol, acyclohexanedimethanol, a polyethyleneglycol, a polypropyleneglycol, andcombinations thereof.
 7. The dosage form of claim 1, wherein thepolyoxaester comprises condensation products of a mixture comprising apolyglycolic diacid and an ethyleneglycol.
 8. The dosage form of claim7, wherein the mixture further comprises a 3,6,9-trioxaundecanedioicdiacid.
 9. The dosage form of claim 7, wherein the polyoxaester has amolecular weight of from approximately 1,000 to approximately 100,000.10. The dosage form of claim 1, wherein the polyoxaester comprisescondensation products of a mixture comprising a3,6,9-trioxaundecanedioic diacid and an ethyleneglycol.
 11. The dosageform of claim 10, wherein the polyoxaester has a molecular weight offrom approximately 1,000 to approximately 100,000.
 12. The dosage formof claim 1, wherein the suspending vehicle consists essentially of thepolyoxaester.
 13. The dosage form of claim 1, wherein the osmotic pumpcomprises a piston and a fluid-imbibing agent.
 14. The dosage form ofclaim 1, wherein the pharmaceutical suspension is substantiallyhomogeneous for at least 6 months.
 15. The dosage form of claim 1,wherein the pharmaceutical suspension is substantially homogeneous forat least 1 year.
 16. The dosage form of claim 1, wherein thepharmaceutical suspension comprises from about 0.1% to about 30% ofparticles by weight.
 17. The dosage form of claim 1, wherein thepharmaceutical suspension comprises from about 0.5% to about 15% ofparticles by weight.